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Process for the preparation and particle size reduction of pirfenidone

Active Publication Date: 2018-11-22
LAURUS LABS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a way to make sensitive materials like pirfenidone smaller using wet mill techniques. This avoids the drawbacks of dry milling. Specifically, the invention reduces the particle size of pirfenidone to below 500 μm.

Problems solved by technology

According to this patent, purity of dibromobenzene is important, as amount of dibromobenzene impurity in the bromobenzene can lead to dimer type byproducts, which complicate the purification of pirfenidone and difficult to remove from final pirfenidone.
Further states that bromobenzene with less that 0.15% of dibromobenzene is not readily available and moreover expensive when compared with the regular bromobenzene.
Furthermore, the PSDs of both drug substance and excipients can affect drug product manufacturability (e.g., flowability, blend uniformity, compactibility, etc.), which, ultimately, can impact safety, efficacy, and quality of the drug product.
Dry milling process used in the loop mill particle size reduction always generates energetic particles that generate thermal energy which generally leads to explosion or burnings.

Method used

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  • Process for the preparation and particle size reduction of pirfenidone
  • Process for the preparation and particle size reduction of pirfenidone
  • Process for the preparation and particle size reduction of pirfenidone

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of 5-methyl-1H-pyridin-2-one

[0107]DM water (800 ml) was added to concentrated sulfuric acid (227 g) at 0-5° C. and stirred for 15 mins. To this, 2-amino-5-methyl pyridine (100 g) followed by aqueous sodium nitrite (83 g of sodium nitrite dissolved in 200 ml of water) was added at below 10° C. The reaction mass was stirred for an hour at 0-5° C. After the reaction completion, reaction mass temperature was raised to 25-35° C. and stirred for 4 hrs. Aqueous sulphamic acid (26.9 g of sulphamic acid dissolved in 100 ml of water) was added to the reaction mass and stirred for 60 mins at 25-35° C. The reaction mass was cooled to 10-15° C. and pH was adjusted to 7 with aqueous sodium hydroxide solution. The reaction mass was heated to 55-65° C. and extracted with ethyl acetate (6×500 ml). The solvent from the extract was distilled off completely under mild vacuum at below 60° C. Ethyl acetate (200 ml) was added to the obtained residue and the reaction mixture was cooled to 25-35...

example 2

Preparation of Pirfenidone

[0109]A mixture of 5-methyl-1H-pyridin-2-one (100 g), bromo benzene (259 g, comprising greater than 0.2% by weight dibromobenzene isomers) and dimethylformamide (200 ml) were added in to a round bottom flask and stirred up to complete dissolution. Potassium carbonate (254 g) and copper (I) chloride (18.2 g) was added to the above reaction mass and then heated to 130-140° C. The reaction mass was stirred at 130-140° C. for 10 hrs. After the reaction completion, the reaction mass was cooled to 25-35° C. Toluene (500 ml), aqueous sodium chloride (75 g of sodium chloride in 500 ml of water) was added to the reaction mass and stirred for 15-30 mins at 25-35° C. The reaction mass was filtered and the filtrate was allowed to settle. Organic and aqueous layers were separated and the aqueous layer was extracted with toluene. Organic layers combined and was washed with aqueous sodium chloride, treated with carbon and filtered through hyflo. The solvent from the filtr...

example 3

Purification of Pirfenidone (from ethyl acetate).

[0114]A suspension of crude Pirfenidone (50g), contaminated with the dimer impurity (˜0.14% by HPLC) in ethyl acetate (100 mL) was maintained at 65-75° C. till the material completely dissolved. The reaction mass was treated with activated carbon (5g) and filtered through a short bed of Hyflo. The flask was rinsed with hot ethyl acetate (50 mL) and the combined filtrate was partially concentrated, under reduced pressure (till ˜2.0 volumes remaining in the flask), while maintain temperature below 60° C. The mixture was gradually cooled to 30±5° C. and then stirred for another 30-60 min. The suspension was cooled to 0-5° C. and maintained for another 2-3 h, at the same temperature. The precipitated material was filtered and then dried at 60±5° C., for 6-8 h, to afford Pirfenidone as white colored powder. Yield: 45 g, HPLC purity 99.9%; dimer content 0.03%.

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Abstract

The present invention relates to an improved process for the preparation of pure pirfenidone having a particular particle size distribution, a crystalline form of pirfenidone, and pharmaceutical compositions thereof, as well as methods for particle size reduction of pirfenidone, and methods for particle size reduction of pirfenidone by wet milling techniques using colloid mill, ultrasonicator, or high speed homogenizer devices.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS:[0001]This application is a continuation-in-part application based on and claims the benefit of International Application PCT / IB2017 / 050141, filed on Jan. 12, 2017 (published on Jul. 20, 2017), which is itself based on and claims the benefit of Indian Provisional Application No. 201641001390, filed on Jan. 14, 2016, entitled “An improved process for the preparation of pirfenidone.” This application is also based on and claims the benefit of Indian Provisional Application No. 201741044403, filed on Dec. 11, 2017, entitled “Method for particle size reduction of pirfenidone.” The content of each of the above-referenced applications are incorporated by reference herein.FIELD OF THE INVENTION[0002]The present invention relates to an improved process for the preparation of pure pirfenidone. The present invention also relates to a crystalline form of pirfenidone and is pharmaceutical composition thereof.[0003]The present invention also generally rela...

Claims

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Application Information

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IPC IPC(8): C07D213/64
CPCC07D213/64
Inventor BOLLU, RAVINDRA BADUMANDADAPU, VENKATA PRAMOD KUMARINDUKURI, VENKATA SUNIL KUMARCHAVA, SATYANARAYANAGALLA, TIRUMALA RAORAO, JAGADESSWARAVASIREDDI, UMA MAHESWER RAO
Owner LAURUS LABS
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